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Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation
  1. Yanping Wu1,
  2. Haixia Chen1,
  3. Nanxia Xuan1,
  4. Lingren Zhou1,
  5. Yinfang Wu1,
  6. Chen Zhu1,
  7. Miao Li1,
  8. Qingyu Weng1,
  9. Jiaxin Shen1,
  10. Hao Zhang1,
  11. Bin Zhang1,
  12. Fen Lan1,
  13. Lixia Xia1,
  14. Xuefang Xiong2,
  15. Zhouyang Li1,
  16. Yun Zhao1,
  17. Mindan Wu1,
  18. Songmin Ying1,
  19. Wen Li1,
  20. Huahao Shen1,3,
  21. Zhihua Chen1
  1. 1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China
  2. 2Department of Respiratory Medicine, Central Hospital of Lishui City, Lishui, Zhejiang, China
  3. 3State Key Lab for Respiratory Diseases, National Clinical Research Centre for Respiratory Disease, Guangzhou, Guangdong, China
  1. Correspondence to Professor Zhihua Chen; zhihuachen{at}zju.edu.cn; Professor Huahao Shen; huahaoshen{at}zju.edu.cn; Professor Wen Li; liwen{at}zju.edu.cn

Abstract

Introduction Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs).

Methods Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation.

Results Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo.

Conclusions FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

  • allergic lung disease
  • eosinophil biology
  • asthma
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Footnotes

  • YW and HC contributed equally.

  • Contributors ZC, HS and WL designed and supervised the study. YW, HC, NX, LZ, YW, CZ, ML, QW, JS, ZL, YZ and MW performed experiments. XX, HZ, BZ, FL and LX assisted in the collection of human samples. YW, HC and ZC prepared figures and drafted manuscript. SY, WL, HS and ZC analysed data and revised manuscript. All authors approved the final manuscript.

  • Funding This work was supported by the State Key Program (2016YFA0501802 to ZC) from Ministry of Science and Technology of the People’s Republic of China, and the Key Project (81930003 to HS), the Major Research plan (91642202 to WL) and the General Program (81873403 to WL) from National Natural Science Foundation of China.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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